Male factor infertility: What the gynecologist should know

Overview

Infertility is a worldwide problem, and affects an estimated 15% of couples globally, amounting to 48.5 million couples.¹   Limited data available on the regionwise prevalence of infertility suggest that the prevalence of infertility is higher in the underdeveloped nations, probable due to limited availability of diagnostic and therapeutic facilities.²   Infertility may be due to female factors alone (approximately 50% of cases), male factors alone (20-30%) or due to a combination of male and female factors (20-30%).¹   Thus a male factor is directly or indirectly responsible for 40-60% of cases involving reproductive-age couples with fertility-related issues.2

Nevertheless, examination and treatment of the male partner in a case of infertility is often neglected or postponed.²   Evaluation of the male partner concurrently with the female partner is of utmost importance in all cases of infertility and should not be underestimated.³

Infertile couples often first approach a gynecologist for treatment. Because half of all infertility problems stem from male factors, it is crucial for the gynecologist to remain updated on the main conditions that cause male infertility as well as current diagnostic tools and treatment options.⁴   Coordinated evaluation of the infertile male using standardized procedures improves both diagnostic precision and the results of subsequent management in terms of effectiveness, risk and costs.²

In the last two decades, there have been significant developments in the field of male infertility and many old concepts are now challenged. Therefore, it is imperative that male infertility physicians should update the gynecologists about the recent advances in the work-up of infertile men in terms of diagnosis and management. Such cooperation will help improve the standards of care for the infertile couple.⁴

Diagnostic evaluation of the male partner

Evaluation of infertility is indicated for couples who fail to achieve a clinical pregnancy after 12 or more months of regular unprotected intercourse. Evaluation of infertility is also indicated for men who have concerns about their future fertility.⁵

At a minimum, initial screening of the male partner of an infertile couple should include a detailed reproductive history and examination of at least one semen sample. The reproductive history should include⁵:

• Coital frequency and timing;
• Duration of infertility and previous fertility;
• Childhood illnesses and developmental history;
• Systemic medical illnesses (such as diabetes mellitus);
• Medications and allergies;
• Personal history (including history of smoking and alcohol consumption);
• Sexual history (including sexually transmitted infections); and
• Exposure to gonadotoxins (including environmental and chemical toxins and heat).

Environmental and life style factors (including obesity, smoking and alcohol consumption) are known to adversely affect sperm parameters thereby contributing to male infertility. Exposure to air pollution has been linked to alterations in sperm parameters. Air pollution, usually associated with increased air content of carbon monoxide (CO), nitrous dioxide (NO₂), sulfur dioxide (SO₂), ozone, lead, and particulate matter in the respirable range (PM 2.5) which can carry multiple trace elements and Polycyclic Aromatic Hydrocarbons (PAHs), is known to disrupt both the hypothalamic-pituitary axis and testicular spermatogenesis and have the potential for causing sperm alterations. Additionally, some studies have suggested that environmental toxins alter sperm DNA integrity.⁶

Cigarette smoking is known to affect semen quality. While 39% of non-smokers show normozoospermia, only 3% of smokers are normozoospermics. Light smokers predominantly show asthenozoospermia, while heavy smokers show asthenozoospermia, teratozoospermia and oligozoospermia.⁷

Numerous drugs and medications have been shown to have adverse effects on male fertility. These include antidepressants, antiepileptics and antibiotics including sulfasalazine, tetracycline derivatives, penicillin group, aminoglycosides (Gentamycin and neomycin).^8,9,10  

There is evidence in literature that type 2 diabetes mellitus has a detrimental effect on semen parameters. A recent study undertaken by Singh et al. compared the seminogram parameters in diabetics and non-diabetics. They found that sperm concentration was 24.6 millions/ml in the diabetic group vs 42.7 millions/ml in non-diabetic group. They also found that diabetes adversely affected sperm motility and sperm morphology (Figure 1).¹¹

A detailed reproductive history is crucial to ascertain an organic cause of infertility. Hence, it is important to ask about coital frequency and timing as well as the duration of infertility. However, the evaluation of primary male infertility (never having fathered a pregnancy) and secondary male infertility (having previously fathered a pregnancy) essentially remains the same.⁵

Semen analysis

Semen analysis is of paramount importance in the initial investigation of the male partner and it is often ordered by the gynecologist during the female infertility workup. It helps to assess the severity of the male factor. It is important for doctors to provide the patient standardized instructions for semen collection (summarized in Table 1).⁵

The semen analysis provides information on semen volume as well as sperm concentration, motility and morphology. Lower limits of accepted reference values for semen analysis (WHO, 2010) are given in Table 2. The diagnosis of azoospermia (complete absence of sperms in semen) should be established only after the specimen is centrifuged (preferably at 3,000g) for 15 minutes and the pellet is examined. Strict sperm morphology helps identify couples who are likely to fail standard in vitro fertilization (IVF) techniques and thus may be ideal candidates for intracytoplasmic sperm injection (ICSI).⁵

However, it must be remembered here that semen analysis should function only as an initial screening tool for assessment of male factor infertility. This is because, while each of the sperm parameters can predict ‘fertility’ and ‘subfertility’, none is a powerful discriminator. It is also important to emphasize that the normal reference values for the semen parameters do not reflect the normal values in the general population nor do they reflect the minimum values required for conception and that men with values outside the normal range may still be fertile, and conversely, men with values within the normal range may still be infertile.⁵   Hence, males with abnormal semen parameters as well as those unable to father a pregnancy despite normal semen parameters should be referred to a andrologist/urologist for a detailed work-up.

A brief note on management

The basic approach towards management of male infertility includes confirmation of diagnosis and to determining the etiology for which pathological, endocrinological and biochemical tests are essential. Various studies show that the commonest cause of male infertility is idiopathic (oligoasthenozoospermia accounting for > 50% cases).¹²   Treatments are therefore directed at improvement of seminal parameters. The empirical medical treatment with or without assisted reproductive techniques appears common in male infertility practice. This type of management can be classified as hormonal treatment including gonadotropins, antiestrogens, and aromatase inhibitors and support with antioxidant supplements such as carnitine, lycopene, glutathione, and vitamin E.¹³   Various approaches to the management of male infertility are depicted in Figure 2.

Medical management of male infertility

Clomiphene citrate

Clomiphene citrate (CC), a selective estrogen receptor modulator, is used to treat unexplained infertility, oligo and asthenospermia, hypogonadism, and nonobstructive azoospermia.¹⁴   CC binds competitively to estrogen on its receptors at the hypothalamus and pituitary gland. After CC administration, the pituitary perceives less estrogen that leads to the secretion of both FSH and LH. The latter binds to LH receptors in the Leydig cells and induces androgen production. As a result, there is a rise in testosterone levels and improved spermatogenesis.¹⁵   Among the various preparations available micronised clomiphene citrate offers the best results due to the advantages illustrated in Table 3

Gonadotropins

Human chorionic gonadotropin (hCG), a glycoprotein similar to endogenous LH, is used to treat nonobstructive azoospermia. hCG binds to the same LH receptor at the Leydig cell level and also stimulates the production of androgens. hCG suppresses endogenous FSH levels through a negative feedback mechanism of elevated serum testosterone. Such an effect may be beneficial since high plasma FSH levels lead to down-regulation of FSH receptors, which has been associated with impaired function of the seminiferous tubules. Increased endogenous androgen levels also restore the function of the sertoli cells that support male germ cell development and survival.¹⁵

Aromatase inhibitors

Aromatase inhibitors (AIs) block the aromatase enzyme, which is present in the adipose tissue, liver, testis and skin, and is responsible for converting testosterone and other androgens to estradiol. The resulting rise in endogenous testosterone levels improves the function of the seminiferous tubules and sperm development and survival. An imbalance in testosterone to estradiol (T/E) ratio, which is frequently seen in obese men, may be reversed by oral administration of AI.¹⁵

When medical management fails the main approach remains intra-uterine insemination (IUI) and assisted reproductive techniques (ART) e.g., in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI).¹²   For mild to moderate male factor infertility, IUI combined with superovulation is often the initial procedure employed. If unsuccessful, IVF or one of its variations is considered. With severe male factor cases, couples are directly advised IVF or one of its variations.¹⁶

Conclusion

Infertility, defined as inability of the couple to conceive after one or more year of unprotected intercourse, affects 8-15% of couples. A male factor is directly responsible for ~20% of infertile couples and contributes in another 30-40% of couples with fertility-related issues.⁵   Semen analysis should be ordered as an initial test in all cases of infertility and it helps to determine the cause and severity of male factor infertility. However, semen analysis should function as only an initial screening tool and thorough evaluation by an urologist should be carried out in all cases with an abnormal semen analysis. Treatment of male infertility involves: medical management, surgical management and ART. For medical management, drugs commonly used are clomiphene, gonadotrophins, bromocriptine, L-thyroxine, vitamin E, B12, etc. For couples in whom improvement in spermatogenesis is not possible or is unsuccessful in producing conception, ARTs offer much promise.

References

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2. Esteves SC, Miyaoka R, Agarwal A. An update on the clinical assessment of the infertile male. Clinics (Sao Paulo). 2011;66(4):691- 700.
3. Schlegel PN. Evaluation of male infertility. Minerva Ginecol. 2009;61(4):261-83.
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6. Najafi FT, Roudsari LR, Namvar F, Ghanbarabadi GV, Talasaz HZ, Esmaeli M. Air pollution and quality of sperm: a meta-analysis. Iran Red Crescent Med J. 2015 Apr 25;17(4):e26930. doi: 10.5812/ ircmj.17(4)2015.26930. eCollection 2015.
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11. Singh AK, Tomarz S, Chaudhari AR, Sinqh R, Verma N. Type 2 diabetes mellitus affects male fertility potential. Indian J Physiol Pharmacol. 2014 Oct-Dec;58(4):403-6.
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13. Gudeloglu A, Brahmbhatt JV, Parekattil SJ. Medical management of male infertility in the absence of a specific etiology. Semin Reprod Med. 2014 Jul;32(4):313-8.
14. Roth LW, Ryan AR, Meacham RB. Clomiphene citrate in the management of male infertility. Semin Reprod Med. 2013 Jul;31(4):245-50.
15. Esteves SC. Clinical management of infertile men with nonobstructive azoospermia. Asian J Androl. 2015 May- Jun;17(3):459-70. doi: 10.4103/1008-682X.148719.
16. Sigman M. Assisted reproductive techniques and male infertility. Urol Clin North Am. 1994 Aug;21(3):505-15.